American Chemical Society
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Structural and Computational Bases for Dramatic Skeletal Rearrangement in Anditomin Biosynthesis

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journal contribution
posted on 2018-07-04, 00:00 authored by Yu Nakashima, Takaaki Mitsuhashi, Yudai Matsuda, Miki Senda, Hajime Sato, Mami Yamazaki, Masanobu Uchiyama, Toshiya Senda, Ikuro Abe
AndA, an Fe­(II)/α-ketoglutarate (αKG)-dependent enzyme, is the key enzyme that constructs the unique and congested bridged-ring system of anditomin (1), by catalyzing consecutive dehydrogenation and isomerization reactions. Although we previously characterized AndA to some extent, the means by which the enzyme facilitates this drastic structural reconstruction have remained elusive. In this study, we have solved three X-ray crystal structures of AndA, in its apo form and in the complexes with Fe­(II), αKG, and two substrates. The crystal structures and mutational experiments identified several key amino acid residues important for the catalysis and provided insight into how AndA controls the reaction. Furthermore, computational calculations validated the proposed reaction mechanism for the bridged-ring formation and also revealed the requirement of a series of conformational changes during the transformation.